This invention relates to a process for preparing a compound of Formula I, 
wherein R1, R2, and Pt are as defined below, which can be used to prepare certain growth hormone secretagogues of Formula II below. This invention also relates to processes for preparing said growth hormone secretagogues.
The compounds of Formula II wherein R1 and R2 are as defined below are potent growth hormone secretagogues. These compounds and their preparation have been disclosed in International patent publication WO98/58947. 
This invention is directed to a compound of Formula VII, 
wherein
Pt is an amine protecting group.
A preferred compound of Formula VII is the compound wherein Pt is Boc.
This invention is also directed to a process, designated Process A, for preparing a compound of Formula III, 
wherein
Pt is an amine protecting group;
R2 is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, xe2x80x94(C1-C4)alkyl-A1 or A1;
A1 for each occurrence is independently selected from the group consisting of (C5-C7)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 for each occurrence is independently optionally substituted, on one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, xe2x80x94OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, xe2x80x94S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, xe2x80x94N(X6)(X6), xe2x80x94N(X6)C(O)(X6), xe2x80x94S(O)2N(X6)(X6), xe2x80x94N(X6)S(O)2-phenyl, xe2x80x94N(X6)S(O)2X6, xe2x80x94CONX11X12, xe2x80x94S(O)2NX11X12, xe2x80x94NX6S(O)2X12, xe2x80x94NX6CONX11X12, xe2x80x94NX6S(O)2NX11X12, xe2x80x94NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 (C1-C10)alkanoyloxy groups or 1 to 3 (C1-C6)alkoxy groups;
X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, the X12 group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
or X11 and X12 are taken together to form xe2x80x94(CH2)rxe2x80x94L1xe2x80x94(CH2)rxe2x80x94;
L1 is C(X2)(X2), O, S(O)m or N(X2);
X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently mono- or di-substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester or 1H-tetrazol-5-yl; or
when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX7 as a ring member;
r for each occurrence is independently 1, 2 or 3;
comprising reacting a compound of Formula IV, 
wherein R3 is (C1-C4)alkyl and Pt is as defined above,
with a preformed isocyanate or a carbonyl equivalent and R2NH2, wherein R2 is as defined hereinabove, in a reaction inert solvent for about one hour to about 72 hours at a temperature of about 0xc2x0 C. to about 80xc2x0 C.
A preferred process within Process A, designated Process B, comprises the process wherein R2 is hydrogen, (C1-C8)alkyl or xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with 1, 2 or 3 fluorine and wherein Pt is tert-butyloxycarbonyl.
A preferred process within Process B, designated Process C, comprises the process wherein said compound of Formula IV is reacted with a carbonyl equivalent selected from carbonyldiimidazole, phosgene, triphosgene and diphosgene.
A preferred process within Process C, designated Process D, comprises the process wherein said carbonyl equivalent is carbonyldiimidazole and said reaction inert solvent is methylene chloride.
A preferred process within Process D, designated Process E, comprises the process wherein R2 is methyl, ethyl or 2,2,2-trifluoroethyl.
An especially preferred process within Process E is the process wherein R2 is methyl.
Another especially preferred process within Process E is the process wherein R2 is ethyl.
Yet another especially preferred process within Process E is the process wherein R2 is 2,2,2-trifluoroethyl.
This invention is also directed to a process, designated Process F, for preparing a compound of Formula I, 
wherein
R1 is xe2x80x94(CH2)qN(X6)C(O)X6, xe2x80x94(CH2)qN(X6)C(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)S(O)2(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)S(O)2X6, xe2x80x94(CH2)qN(X6)C(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qC(O)OX6, xe2x80x94(CH2)qC(O)O(CH2)txe2x80x94A1, xe2x80x94(CH2)qOX6, xe2x80x94(CH2)qOC(O)X6, xe2x80x94(CH2)qOC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qOC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qOC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)X6, xe2x80x94(CH2)qC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)OX6, xe2x80x94(CH2)qN(X6)S(O)2N(X6)(X6), xe2x80x94(CH2)qS(O)mX6, xe2x80x94(CH2)qS(O)m(CH2)txe2x80x94A1, xe2x80x94(C1-C10)alkyl, xe2x80x94(CH2)qxe2x80x94A11, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94A1 or xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94(C3-C7)cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;
Y1 is O, S(O)m, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94N(X6)C(O)xe2x80x94, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)N(X6)xe2x80x94 or xe2x80x94OC(O)xe2x80x94;
q is 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
said (CH2)q group and (CH2)t group in the definition of R1 are optionally independently substituted with hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C1-C4)alkyl groups; and
R2 is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, xe2x80x94(C1-C4)alkyl-A1 or A1;
where the alkyl groups and the cycloalkyl groups in the definition of R1 are optionally substituted with hydroxy, xe2x80x94C(O)OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94N(X6)(X6), xe2x80x94N(X6)X6, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)A1, xe2x80x94C(O)(X6), CF3, CN or 1, 2 or 3 independently selected halo groups;
A1 for each occurrence is independently selected from the group consisting of (C5-C7)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 for each occurrence is independently optionally substituted, on one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, xe2x80x94OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, xe2x80x94S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, xe2x80x94N(X6)(X6), xe2x80x94N(X6)C(O)(X6) , xe2x80x94S(O)2N(X6)(X6), xe2x80x94N(X6)S(O)2-phenyl, xe2x80x94N(X6)S(O)2X6, xe2x80x94CONX11X12, xe2x80x94S(O)2NX11X12, xe2x80x94NX6S(O)2X12, xe2x80x94NX6CONX11X12, xe2x80x94NX6S(O)2NX11X12, xe2x80x94NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 (C1-C10)alkanoyloxy groups or 1 to 3 (C1-C6)alkoxy groups;
X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, the X12 group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
or X11 and X12 are taken together to form xe2x80x94(CH2)rxe2x80x94L1xe2x80x94(CH2)rxe2x80x94;
L1 is C(X2)(X2), O, S(O)m or N(X2);
X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently mono- or di-substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester or 1H-tetrazol-5-yl; or
when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX7 as a ring member;
r for each occurrence is independently 1, 2 or 3;
X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1 to 5 halo groups or 1-3 OX3 groups;
X3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy;
m for each occurrence is independently 0, 1 or 2;
provided that X6 and X12 cannot be hydrogen when attached to C(O) or S(O)2 in the form C(O)X6, C(O)X12, S(O)2X6 or S(O)2X12; and
Pt is an amine protecting group;
comprising reacting a compound of Formula III, 
wherein Pt and R2 are as defined hereinabove,
with an alkylating agent of formula R1xe2x80x94Z, wherein R1 is as defined hereinabove and Z is a leaving group, in the presence of a suitable base and a reaction inert solvent.
A preferred process within Process F, designated Process G, comprises the process wherein R1 is xe2x80x94(CH2)qxe2x80x94A1 or (C1-C7)alkyl; and R2 is hydrogen, (C1-C8)alkyl or xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with 1, 2 or 3 fluorine and wherein Pt is tert-butyloxycarbonyl.
A preferred process within Process G, designated Process H, comprises the process wherein Z in said alkylating agent is p-toluenesulfonyloxy, methanesulfonyloxy or halo; said base is alkaline metal bis(trimethylsilyl)amide or alkaline alkoxide; and said reaction inert solvent is N,N-dimethylformamide, tetrahydrofuran, toluene, isopropyl ether, MTBE or a mixture thereof.
A preferred process within Process H, designated Process I, comprises the process wherein R1 is xe2x80x94CH2xe2x80x94A1, Z is Cl, Br or I, R2 is hydrogen or (C1-C3)alkyl optionally substituted with 1, 2 or 3 fluoro groups.
A preferred process within Process I, designated Process J, comprises the process wherein A1 is phenyl, pyridyl or thiazolyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH3, OCF2H, OCF3 and CF3; and R2 is methyl, ethyl or 2,2,2-trifluoroethyl.
An especially preferred process within Process J is the process wherein R1 is pyridin-2-ylmethyl or benzyl, where said benzyl is optionally substituted with up to two fluoro, chloro or trifluoromethyl; and R2 is methyl.
Another especially preferred process within Process J is the process wherein R1 is pyridin-2-ylmethyl or benzyl, where said benzyl is optionally substituted with up to two fluoro, chloro or trifluoromethyl; and R2 is ethyl.
Yet another especially preferred process within Process J is the process wherein R1 is pyridin-2-ylmethyl or benzyl, where said benzyl is optionally substituted with up to two fluoro, chloro or trifluoromethyl; and R2 is 2,2,2-trifluoroethyl.
This invention is also directed to a process, designated Process K, for preparing a compound of Formula V, 
wherein
R1 is xe2x80x94(CH2)qN(X6)C(O)X6, xe2x80x94(CH2)qN(X6)C(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)S(O)2(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)S(O)2X6, xe2x80x94(CH2)qN(X6)C(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qC(O)OX6, xe2x80x94(CH2)qC(O)O(CH2)txe2x80x94A1, xe2x80x94(CH2)qOX6, xe2x80x94(CH2)qOC(O)X6, xe2x80x94(CH2)qOC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qOC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qOC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)X6, xe2x80x94(CH2)qC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)OX6, xe2x80x94(CH2)qN(X6)S(O)2N(X6)(X6), xe2x80x94(CH2)qS(O)mX6, xe2x80x94(CH2)txe2x80x94A1, xe2x80x94(C1-C10)alkyl, xe2x80x94(CH2)qxe2x80x94A1, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94A1 or xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94(C3-C7)cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2,
xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;
Y1 is O, S(O)m, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94N(X6)C(O)xe2x80x94, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)N(X6)xe2x80x94 or xe2x80x94OC(O)xe2x80x94;
q is 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
said (CH2)q group and (CH2)t group in the definition of R1 are optionally independently substituted with hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C1-C4)alkyl groups; and
R2 is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, xe2x80x94(C1-C4)alkyl-A1 or A1;
where the alkyl groups and the cycloalkyl groups in the definition of R1 are optionally substituted with hydroxy, xe2x80x94C(O)OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94N(X6)(X6),
xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)A1, xe2x80x94C(O)(X6), CF3, CN or 1, 2 or 3 independently selected halo groups;
A1 for each occurrence is independently selected from the group consisting of (C5-C7)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 for each occurrence is independently optionally substituted, on one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, xe2x80x94OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, xe2x80x94S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, xe2x80x94N(X6)(X6), xe2x80x94N(X6)C(O)(X6), xe2x80x94S(O)2N(X6)(X6), xe2x80x94N(X6)S(O)2-phenyl, xe2x80x94N(X6)S(O)2X6, xe2x80x94CONX11X12, xe2x80x94S(O)2NX11X12, xe2x80x94NX6S(O)2X12, xe2x80x94NX6CONX11X12, xe2x80x94NX6S(O)2NX11X12, xe2x80x94NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 (C1-C10)alkanoyloxy groups or 1 to 3 (C1-C6)alkoxy groups;
X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, the X12 group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
or X11 and X12 are taken together to form xe2x80x94(CH2)rxe2x80x94L1xe2x80x94(CH2)rxe2x80x94;
L1 is C(X2)(X2), O, S(O)m or N(X2);
X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently mono- or di-substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester or 1H-tetrazol-5-yl; or
when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX7 as a ring member;
r for each occurrence is independently 1, 2 or 3;
X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1 to 5 halo groups or 1-3 OX3 groups;
X3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy;
m for each occurrence is independently 0, 1 or 2;
provided that X6 and X12 cannot be hydrogen when attached to C(O) or S(O)2 in the form C(O)X6, C(O)X12, S(O)2X6 or S(O)2X12;
comprising reacting a compound of Formula I, 
wherein Pt is an amine protecting group and R1 and R2 are as defined hereinabove;
with an acid in the presence of a reaction inert solvent.
A preferred process within Process K, designated Process L, comprises the process wherein R1 is xe2x80x94(CH2)qxe2x80x94A1 or (C1-C7)alkyl; and R2 is hydrogen, (C1-C8)alkyl or xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with 1, 2 or 3 fluorine and wherein Pt is t-butyloxycarbonyl.
A preferred process within Process L, designated Process M, comprises the process wherein said acid is methanesulfonic acid, and said reaction inert solvent is methylene chloride.
A preferred process within Process M, designated Process N, comprises the process wherein is R1 is xe2x80x94CH2xe2x80x94A1; and R2 is hydrogen or (C1-C3)alkyl optionally substituted with 1, 2 or 3 fluoro groups.
A preferred process within Process N, designated Process O, comprises the process wherein R1 is xe2x80x94CH2xe2x80x94A1 where A1 is phenyl, pyridyl or thiazolyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH3, OCF2H, OCF3 and CF3; and R2 is methyl, ethyl or 2,2,2-trifluoroethyl.
An especially preferred process within Process O comprises the process wherein R1 is pyridin-2-ylmethyl or benzyl, where said benzyl is optionally substituted with up to two fluoro, chloro or trifluoromethyl and particularly where said benzyl is substituted with up to two fluoro; and R2 is methyl. Still more especially preferred within this process is the process wherein R1 is benzyl and R2 is methyl or where R1 is pyridin-2-ylmethyl and R2 is methyl.
Another especially preferred process within Process O comprises the process wherein R1 is pyridin-2-ylmethyl or benzyl, where said benzyl is optionally substituted with up to two fluoro, chloro or trifluoromethyl; and R2 is ethyl. Still more especially preferred within this process is the process wherein R1 is benzyl and R2 is ethyl or where R1 is pyridin-2-ylmethyl and R2 is ethyl.
Yet another especially preferred process within Process O comprises the process wherein R1 is pyridin-2-ylmethyl or benzyl, where said benzyl is optionally substituted with up to two fluoro, chloro or trifluoromethyl; and R2 is 2,2,2-trifluoroethyl. Still more especially preferred within this process is the process wherein R1 is benzyl and R2 is trifluoroethyl or where R1 is pyridin-2-ylmethyl and R2 is trifluoroethyl.
This invention is also directed to a process, designated Process P, for preparing a compound of Formula XIII, 
comprising:
(a) reacting piperazine-1,3-dicarboxic acid 1-tert-butyl ester 3-(C1-C4)alkyl ester with a carbonyl equivalent and 2,2,2-trifluoroethylamine in the presence of a reaction inert solvent to form the compound of Formula XIV, 
(b) reacting said compound of Formula XIV with 2-picolyl-Z1, wherein Z1 is halo, methanesulfonyloxy or p-toluenesulfonyloxy, in the presence of a base and a reaction inert solvent to form the compound of Formula XV, 
(c) reacting said compound of Formula XV with an acid in the presence a reaction inert solvent.
A preferred process within Process P, designated Process Q, comprises the process wherein in step (a), said carbonyl equivalent is N,Nxe2x80x2-carbonyldiimidazole, phosgene, diphosgene or triphosgene and said reaction inert solvent is methylene chloride; in step (b), said alkylating agent is 2-picolyl chloride, said base is potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodium amide, potassium amide, sodium (C1-C4)alkoxide or potassium (C1-C4)alkoxide and said reaction inert solvent is a mixture of tetrahydrofuran and N,N-dimethylformamide; and in step (c), said acid is methanesulfonic acid and said reaction inert solvent is, methylene chloride.
A preferred process within Process Q is the process wherein in step (a), said carbonyl equivalent is N,Nxe2x80x2-carbonyldiimidazole; and in step (b), said base is potassium bis(trimethylsilyl)amide.
This invention is also directed to a process, designated Process R, for preparing a compound of Formula VI, 
comprising
(a) reacting a compound of Formula IV, 
wherein Pt is an amine protecting group and R3 is (C1-C4)alkyl,
with a carbonyl equivalent and CF3CH2NH2 in a reaction inert solvent to form a compound of Formula VII, 
xe2x80x83wherein Pt is as defined hereinabove;
(b) reacting said compound of Formula VII with 2-picolyl-Z1, wherein Z1 is halo, methanesulfonyloxy or p-toluenesulfonyloxy, in the presence of a base and a reaction inert solvent at a temperature from about xe2x88x9278xc2x0 C. to about 25xc2x0 C. for from about one hour to about 24 hours to form a compound of Formula VIII, 
wherein Pt is as defined above;
(c) reacting said compound of Formula VIII with a suitable acid in a reaction inert solvent at a temperature from about xe2x88x9230xc2x0 C. to about 25xc2x0 C. for from about one hour to about 10 hours to form a compound of Formula IX, 
(d) resolving said compound of Formula IX with D-tartaric acid in a reaction inert solvent to form the D-tartrate salt of a compound of Formula X, 
(e) reacting said D-tartrate salt of a compound of Formula X with a compound of Formula XI, 
wherein Boc is tert-butyloxycarbonyl, a peptide coupling reagent and a base in a reaction inert solvent to form a compound of Formula XII, 
(f) reacting said compound of Formula XII under standard t-butyloxycarbonyl group removing conditions to form a compound of Formula VI, 
A preferred process within Process R, designated Process S, is the process wherein:
in step (a), said carbonyl equivalent is N,Nxe2x80x2-carbonyldiimidazole, phosgene, diphosgene or triphosgene;
in step (b), said base is potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodium amide, potassium amide, sodium (C1-C4)alkoxide or potassium (C1-C4)alkoxide and
in step (e), said peptide coupling reagent is EEDQ, EDC, DCC or 1-propanephosphonic acid cyclic anhydride;
A preferred process within Process S, designated Process T, is the process wherein:
in step (a), said carbonyl equivalent is N,Nxe2x80x2-carbonyidiimidazole and said reaction inert solvent is methylene chloride;
in step (b), said base is potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and said reaction inert solvent is N,N-dimethylformamide, toluene, tetrahydrofuran or a mixture thereof;
in step (c), said acid is methanesulfonic acid and said reaction inert solvent is methylene chloride;
in step (d), said reaction inert solvent is a mixture of acetone and water;
in step (e), said peptide coupling reagent is 1-propanephosphonic acid cyclic anhydride, said base is triethylamine and said reaction inert solvent is ethyl acetate; and
in step (f), said standard t-butyloxycarbonyl group removing conditions comprise using hydrochloric acid in methanol.
This invention is particularly directed to a process of Process T wherein 2-amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide is prepared.